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1521-009X/46/8/1212–1225$35.00 https://doi.org/10.1124/dmd.117.079038 AND DISPOSITION Drug Metab Dispos 46:1212–1225, August 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Minireview

The Drug- Potential of Antiviral Agents for the Treatment of Chronic C

Kimberly L. Garrison, Polina German, Erik Mogalian, and Anita Mathias Inc., Foster City, California

Received October 18, 2017; accepted March 26, 2018

ABSTRACT Downloaded from Several safe and highly effective direct-acting antiviral (DAA) drugs plus with or without ), the potential for drug-drug for chronic (HCV) have been developed and greatly interactions (DDIs) becomes an important consideration for HCV- increase the number of therapeutic options available to successfully infected individuals with comorbidities that require concomi- treat HCV infection. However, because treatment regimens contain tant , such as human immunodeficiency virus/HCV at least two drugs (e.g., and , and coinfection or after transplantation. This , or with , , , or review details the and DDI potential of approved dmd.aspetjournals.org ) and up to five drugs (ombitasvir// DAAs for the treatment of HCV infection.

Introduction medications were associated with frequent adverse effects and in- Chronic (HCV) is a global health problem affecting an adequate antiviral efficacy (assessed as sustained virologic response). In 2013, the U.S. Food and Drug Administration approved the first direct- estimated 71 million people worldwide (http://www.who.int/mediacentre/ at ASPET Journals on September 28, 2021 factsheets/fs164/en/). In the United States, an estimated 2.7–3.9 million acting antiviral (DAA) protease inhibitors, and . people have chronic HCV infection, which causes more than 19,000 When administered with Peg-IFN plus ribavirin, boceprevir- and deaths annually http://www.euro.who.int/en/health-topics/communi- telaprevir-containing regimens resulted in higher sustained virologic cable-diseases/hepatitis/data-and-statistics, although under-reporting response rates compared with Peg-IFN plus ribavirin monotherapy, but may contribute to an underestimation by up to 5-fold (Mahajan et al., the safety and efficacy of these regimens remained suboptimal. Since 2014). In the European Region, approximately 15 million people have then, many highly effective and well tolerated DAA regimens have been chronic HCV infection, which results in 86,000 deaths annually in WHO developed, consisting of various combinations of nucleotide analog European Member States. (http://www.who.int/mediacentre/factsheets/ NS5B inhibitors, non-nucleotide NS5B inhibitors, NS5A inhibitors, fs164/en/). After acute infection with HCV, approximately 75%–85% of and/or NS3/4A protease inhibitors, including simeprevir, daclatasvir, individuals fail to spontaneously clear the virus and thus progress to sofosbuvir, ledipasvir/sofosbuvir, /paritaprevir/ritonavir plus chronic infection. Complications of chronic HCV infection include liver dasabuvir, sofosbuvir/velpatasvir, elbasvir/grazoprevir, sofosbuvir/ , end-stage liver disease, and hepatocellular carcinoma; in the velpatasvir/, and glecaprevir/pibrentasvir. The combination United States, HCV remains one of the leading indications for liver therapies now achieve cure rates approaching 100%, and regimens have transplantation (Kim et al., 2017). Almost three-quarters of the reported even become available for those patients who fail the available, highly HCV-related deaths in the United States have occurred in the baby effective DAA regimens (Vosevi, 2017a,b). boomer generation, with a median age at death (57 years) that is Given the significant and rapid advancements in highly effective approximately 20 years less than the average lifespan for the general treatment options, boceprevir and telaprevir (which are no longer population (Smith et al., 2012). available commercially) and (an NS3 protease inhibitor, Prior to 2011, the standard of care for treating HCV included which is only approved for use in China and Japan) will not be further administration of pegylated- (Peg-IFN) and ribavirin. These discussed in this article. The availability of highly effective and well tolerated DAA regimens The work was supported by Gilead Sciences Inc. represents a significant advancement for patients with chronic HCV https://doi.org/10.1124/dmd.117.079038. infection; however, the potential for metabolic or transport-mediated

ABBREVIATIONS: 3TC, lamivudine; ABC, abacavir; ALT, alanine aminotransferase; ARV, antiretroviral; ATV, atazanavir; AUC, area under the plasma concentration versus time curve; BCRP, breast cancer resistance protein; COBI, cobicistat; DAA, direct-acting antiviral; DDI, drug-drug interaction; DRV, darunavir; DTG, dolutegravir; EE, ethinyl ; EFV, ; EVG, elvitegravir; FTC, emtricitabine; GS-331007, 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4-dione; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LPV, lopinavir; MRP, multidrug resistance protein; NRTI, nucleoside or nucleotide reverse transcriptase inhibitor; OATP, organic anion-transporting polypeptide; P-gp, p-glycoprotein; P450, ; Peg-IFN, pegylated-interferon; RAL, raltegravir; RPV, rilpivirine; SmPC, European Summary of Product Characteristics; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; UGT, glucuronosyltransferase; USPI, U.S. Prescribing Information.

1212 The DDI Potential of HCV DAAs 1213 drug-drug interactions (DDIs) warrants consideration because these 1, 4, 5, or 6 infection. Ledipasvir/sofosbuvir is administered treatment regimens contain at least two drugs (e.g., ledipasvir/sofosbuvir) once daily without regard to food (Harvoni, 2017a,b). Ledipasvir is and up to five drugs (ombitasvir/paritaprevir/ritonavir plus dasabuvir primarily excreted unchanged in bile, with ,1% excreted in urine plus ribavirin). Careful thought about possible DDIs is especially (Kirby et al., 2013). Ledipasvir is both a substrate and an inhibitor of important for patients with chronic conditions such as human P-gp/BCRP; ledipasvir does not inhibit or induce cytochrome P450 immunodeficiency virus (HIV)/HCV coinfection, individuals who (P450) enzymes or uridine glucuronosyltransferases (UGTs) (German receive immunosuppressive therapy after , or et al., 2014b). patients with other comorbidities that require concomitant . This review details the pharmacokinetics and DDI potential of currently Ombitasvir/Paritaprevir/Ritonavir With or Without Dasabuvir approved DAAs for the treatment of HCV infection. The combination of ombitasvir (25 mg), an NS5A inhibitor, with a ritonavir (100 mg)–boosted NS3/4A protease inhibitor, paritaprevir Summary of DAA Characteristics (150 mg), plus a non-nucleotide NS5B inhibitor, dasabuvir (150 mg twice daily), with or without ribavirin (with food) is approved for Below is a list of DAAs available as single agents (to be used in treatment of HCV genotype 1 infection (Viekira Pak, 2017; Viekirax, combination with other DAAs) or as complete treatment regimens. 2018). Ombitasvir/paritaprevir/ritonavir is also approved for use with Table 1 summarizes clinical and/or nonclinical data characterizing ribavirin against HCV genotype 4 (Technivie, 2016; Viekirax, 2018). DAAs as substrates, inducers, or inhibitors of metabolic enzymes and

Ombitasvir, ritonavir, paritaprevir, and dasabuvir are primarily elimi- Downloaded from transporters. nated in the feces, whereas 1.91%, 8.8%, 11.3%, and approximately 2% of the doses are excreted in the urine, respectively (Viekira Pak, 2017; Simeprevir Viekirax, 2018). Ombitasvir is primarily excreted unchanged, whereas Simeprevir (150 mg), an NS3/4A protease inhibitor, is administered paritaprevir, ritonavir, and dasabuvir are primarily metabolized. Ombi- once daily in combination with sofosbuvir or Peg-IFN plus ribavirin in tasvir is a substrate of amidases, CYP3A, and P-gp/BCRP. Paritaprevir subjects with HCV genotype 1 infection (Olysio, 2017). Simeprevir is is a substrate for CYP3A, P-gp/BCRP, and OATP1B1/3. Dasabuvir dmd.aspetjournals.org dosed with food because food increases its [area under the is a substrate for CYP2C8 and P-gp/BCRP (Menon et al., 2015). plasma concentration versus time curve (AUC)] by 61%–69% (Olysio, Ombitasvir, paritaprevir, and dasabuvir all inhibit UGT1A1 (Viekira 2016, 2017). Simeprevir is primarily eliminated in the feces (91%) Pak, 2017). In addition, paritaprevir inhibits BCRP and OATP1B1/3, predominantly as metabolites, with ,1% excreted in the urine. and dasabuvir inhibits BCRP (Viekira Pak, 2017). To increase its Simeprevir is a substrate of CYP3A, P-glycoprotein (P-gp)/breast cancer systemic exposure, paritaprevir is coadministered with low-dose resistance protein (BCRP), multidrug resistance protein MRP2, and ritonavir (Norvir, 2017). organic anion-transporting polypeptide OATP1B1/3 and inhibits CYP1A2, CYP3A4 (intestinal), P-gp, and OATP1B1/3 (Ouwerkerk- Sofosbuvir/Velpatasvir at ASPET Journals on September 28, 2021 Mahadevan et al., 2016; Olysio, 2017). Velpatasvir (100 mg) is a pangenotypic HCV NS5A inhibitor administered as a fixed-dose combination with sofosbuvir (400 mg; Sofosbuvir presented above) that is approved for treatment of HCV 1, 2, Sofosbuvir, a nucleotide analog prodrug, is converted to the active 3, 4, 5, or 6 and can be taken without regard to food (Epclusa, 2017a,b). triphosphate that directly inhibits HCV NS5B RNA polymerase. Velpatasvir is primarily eliminated unchanged in the feces, with ,1% Sofosbuvir (400 mg) exhibits pangenotypic potency and is indicated excreted renally (Mogalian et al., 2015b). Velpatasvir is a substrate of for use with other DAAs, including simeprevir, daclatasvir, ledipasvir, or P-gp/BCRP, CYP2B6, CYP2C8, and CYP3A4 and inhibits P-gp, velpatasvir (Daklinza, 2017; Epclusa, 2017b; Harvoni, 2017b; Sovaldi, BCRP, and OATP (Mogalian et al., 2016b). Velpatasvir does not 2017a). Sofosbuvir is recommended for administration once daily induce or inhibit P450s or UGTs (Mogalian et al., 2016b). without regard to food in the U.S. Prescribing Information (USPI) and with food in the European Summary of Product Characteristics (SmPC) Elbasvir/Grazoprevir (Sovaldi, 2017a,b). Sofosbuvir is extensively metabolized by hydro- Elbasvir (50 mg), an NS5A inhibitor, and grazoprevir (100 mg), an . lases, and the GS-331007 metabolite accounts for 90% of overall drug NS3/4A protease inhibitor, are approved for treatment of HCV genotype exposure (Kirby et al., 2015). Sofosbuvir (but not GS-331007) is a 1 or 4 infection and can be taken without regard to food (Zepatier, 2017, substrate of P-gp/BCRP. Neither sofosbuvir nor its metabolites inhibit 2018). Elbasvir and grazoprevir are primarily eliminated in the feces, or induce metabolizing enzymes or drug transporters. with ,1% in the urine; both are subject to oxidative metabolism, primarily by CYP3A (Zepatier, 2017, 2018). Elbasvir and grazoprevir Daclatasvir are substrates of CYP3A and P-gp; the role of P-gp in the absorption of Daclatasvir (60 mg) is an NS5A inhibitor approved for use with both drugs appears to be minimal (Zepatier, 2017, 2018). Grazoprevir asunaprevir for HCV genotype 1 (China and Japan) or with sofosbuvir may also be transported by BCRP (Zepatier, 2018). Grazoprevir is a for HCV genotypes 1, 3, or 4 (United States and European Union) substrate of OATP1B1/3 (Zepatier, 2017, 2018). Elbasvir is not a (Daklinza, 2014, 2017). Daclatasvir is administered once daily without CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in regard to food. The primary route of elimination for daclatasvir is the humans (Zepatier, 2017). In vitro, elbasvir inhibits P-gp and both drugs feces (88%), predominantly as the parent, with little renal inhibit BCRP (Zepatier, 2017, 2018). (6.6%). Daclatasvir is a substrate for CYP3A and P-gp and is an inhibitor of P-gp/BCRP and OAT1B1/3 (Garimella et al., 2016; Daklinza, 2017). Sofosbuvir/Velpatasvir/Voxilaprevir The combination sofosbuvir/velpatasvir/voxilaprevir is approved for Ledipasvir/Sofosbuvir treatment of HCV genotypes 1, 2, 3, 4, 5, or 6, including for patients who A fixed-dose combination of NS5A inhibitor ledipasvir (90 mg) and have failed other DAA regimens, and is recommended to be adminis- sofosbuvir (400 mg; presented above) is approved for treatment of HCV tered with food (Vosevi, 2017a,b). The characteristics of sofosbuvir and 1214 Garrison et al.

TABLE 1 Summary of potential DDI mechanisms

HCV DAA

Enzyme or DCV + LDV/SOF OBV/PTV/r 6 DSV EBR/GZR SOF/VEL SOF/VEL/VOX GLE/PIB Transporter SOF SMP SOF DCV LDV OBV PTV RTV DSV EBR GZR VEL VOX GLE PIB BCRP SUB, INH SUB INH SUB, SUB SUB, INH SUB, INHa INHa SUB, SUB, INHa SUB, SUB, INHa INH INH INHa INH INH OATP1B1/1B3 SUB, INH — INH ——SUB, ——— SUB SUB, SUB, INHa SUB, INH INH INHa INH OATP2B1 SUB —— ——INH INH —— — INHa ——— P-gp SUB, INH SUB SUB, SUB, SUB SUB SUB, SUB SUB, SUB SUB, SUB, INHa SUB, SUB, INH INHa INH INH INHa INH INH CYP1A2 INH (weak) —— — c ———— — — SUB INH INH CYP2B6 — ———————— — SUB ——— CYP2C8 ———————SUB ——SUB SUB —— CYP3A4 SUB, INH — SUB, — SUB SUB SUB, — SUB SUB, INH SUB SUB SUB,d INH (weak)a INDb INH (weak) INH

UGT1A1 ————INH INH — INH —— — —INH INH Downloaded from

DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; IND, inducer; INH, inhibitor; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; RTV or/r, ritonavir; SMP, simeprevir; SOF, sofosbuvir; SUB, substrate; VEL, velpatasvir; VOX, voxilaprevir. aLimited primarily to the process of absorption/intestine (Epclusa, 2017; Harvoni, 2017; Zepatier, 2018). bVery weak inducer in vivo with no dose adjustment of substrates needed (Daklinza, 2018). cCYP1A2 substrates may require monitoring (Viekirax, 2018). dmd.aspetjournals.org velpatasvir are presented above. Voxilaprevir is a pangenotypic NS3/4A The AUC and the plasma concentration at the end of the dosing inhibitor that is exclusively eliminated in the feces, with slow meta- interval (Ct) of simeprevir, a substrate for CYP3A and P-gp, were 48% bolic turnover by predominantly CYP3A (Kirby et al., 2016b; Vosevi, and 92% lower, respectively, when coadministered with multiple-dose 2017a,b). Voxilaprevir is a substrate and inhibitor of P-gp, BCRP, and rifampin (600 mg) (Olysio, 2017). An increase in the simeprevir Cmax of OATP1B1/3 (Kirby et al., 2016a; Vosevi, 2017a,b). 31% was observed and attributed to rifampin-mediated OATP inhibition (Ouwerkerk-Mahadevan et al., 2016). Accordingly, the use of simepre-

Glecaprevir/Pibrentasvir vir with moderate to strong CYP3A/P-gp inducers is not recommended at ASPET Journals on September 28, 2021 The combination of NS3/4A inhibitor glecaprevir (100 mg) and (Olysio, 2017). NS5A inhibitor pibrentasvir (40 mg) is approved for treatment of HCV Sofosbuvir, ledipasvir, velpatasvir, daclatasvir, voxilaprevir, glecap- genotype 1, 2, 3, 4, 5, or 6 infection, including patients with genotype revir, and pibrentasvir are P-gp substrates. Velpatasvir (minor), 1 who have failed either an NS5A- or NS3/4a-containing regimen. voxilaprevir (minor), and daclatasvir are also substrates for CYP3A. Biliary excretion is the primary route of elimination for both glecaprevir Consistent with the effect of intestinal efflux transporters on sofosbuvir and pibrentasvir, with 0.7% and 0% excreted in the urine, respectively. pharmacokinetics, rifampin significantly reduced the sofosbuvir AUC Glecaprevir is a substrate of P-gp, BCRP, and OATP1B1/3. Pibrentasvir (72% lower) and Cmax (77% lower); AUC and Cmax values were is a substrate of P-gp, and transport by BCRP could not be excluded. unaltered for GS-331007 (Garrison et al., 2014). Rifampin administra- Both glecaprevir and pibrentasvir are inhibitors of P-gp, BCRP, and tion decreased systemic exposures of NS5A inhibitors ledipasvir, OATP1B1/3, as well as weak inhibitors of CYP3A, CYP1A2, and velpatasvir, daclatasvir, and pibrentasvir. AUC and Cmax values were UGT1A1. 59% and 35% lower for ledipasvir (German et al., 2014b), 82% and 71% lower for velpatasvir (Mogalian et al., 2016b), 79% and 66% lower for DDIs daclatasvir (Daklinza, 2017), and 87% and 83% lower for pibrentasvir (Mavyret, 2017), respectively. Systemic exposures of NS3/4A inhibitors The potential for DDIs has been assessed mechanistically using were also decreased with multiple-dose rifampin. The AUC for established phenotypic probes and was also evaluated clinically using voxilaprevir was 73% lower, whereas the Cmax remained unchanged concomitant medications that may be commonly administered to HCV- (Garrison et al., 2014; Kirby et al., 2016a). AUC and Cmax values were infected patients. These DDI mechanisms and a selection of common 88% and 86% lower for glecaprevir, respectively (Mavyret, 2017). The concomitant medications are highlighted in Tables 2 and 3. Information use of rifampin with sofosbuvir, ledipasvir/sofosbuvir, or sofosbuvir/ pertaining to DDIs between DAAs and HIV antiretroviral (ARV) drugs velpatasvir is not recommended (Epclusa, 2017b; Harvoni, 2017b; is presented in Tables 4 and 5. Sovaldi, 2017b). Use of rifampin with sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir is contraindicated (Mavyret, 2017; Vosevi, Mechanistic DDIs 2017a). Coadministration of daclatasvir with strong CYP3A inducers, DAAs as Victims of Metabolic and/or Transport Inducers. such as rifampin, is contraindicated (Daklinza, 2017). Use of efavirenz Several P450s and drug transporters are involved, to varying extents, in (EFV), a moderate inducer, is not recommended for sofosbuvir/velpa- the disposition of DAAs described above. Inducers of P450 and drug tasvir, sofosbuvir/velpatasvir/voxilaprevir, and glecaprevir/pibren- transporters, such as P-gp, may significantly decrease plasma concen- tasvir; no dose adjustment is needed for ledipasvir/sofosbuvir or trations, thereby leading to a reduced therapeutic effect. Clinical studies sofosbuvir (Epclusa, 2017b; Harvoni, 2017b; Mavyret, 2017; Vosevi, have been conducted to assess the sensitivity of several DAAs to 2017a). Coadministration of daclatasvir with moderate CYP3A inducers metabolic and/or transporter induction using prototypical inducers (e.g., , ; see label) warrants a dose increase to (rifampin or ). 90 mg daclatasvir (Daklinza, 2017). The DDI Potential of HCV DAAs 1215

TABLE 2 Impact of coadministered drugs on DAA exposure (AUC) Data are given in percentages.

LDV/SOF OBV/PTV/DSV/r EBR/GZR SOF/VEL SOF/VEL/VOX GLE/PIB Drug Class SMP SOF DCV LDV OBV PTV DSV /r GZR EBR VEL VOX GLE PIB Immunosuppressants Cyclosporine ↑468a ↑353b — ↑40d ↔↑72 ↑ 30 ↔↑1421c,d ↑98 ↑103b ↑839b ↑408c,d ↑93c —— — —↔↑26 ↔↔ —— —— Mycophenolate mofetil — — — ————— ↓26 ↔ —— —— —— — —↔↑19 ↔↔ —— —— Tacrolimus ↑90a ↑13 —— ↓34 ↔↔ ↔ ↔ —— —— Statins and lipid-lowering agents Atorvastatin — — — ————— ↑26 —— — — — Gemfibrozil —— — ——↑38 ↑1025 ↔ ——— — — — — — — ————— — — — — — — Pitavastatin — — — ————— ↔ —— — — — Pravastatin —— — —↔↔ ↔ ↑24 ↔ —— —— Rosuvastatin —— — —↔↑52 ↔↔ ↔ ↔ —— —— — — — ————— — — — — — — Downloaded from Cardiovascular — — — ————— — — — — — — —— — —↔↓22 ↔↔ ——— — — — —— — —↔ — ↔ ———— — — — —— —↑200 ↔↑98 ↑42 ↑57 ↑202 ↑80 ↑71 ——— — — — ————— — — — ↑84 —— Acid-reducing agents dmd.aspetjournals.org Famotidine — ↔↔↔———— ↔↔↔ ——— — ↔↓4–42c ↔↔↔ ↔ ↔ ——↓26–55c ↔↓29–51c ↔ Pantoprazole — — — ————— ↔↔—— —— Antibacterial agents ↑647 — — ————— — — — — — — Rifampin ↓48 ↓72 ↓59 ↓79 ———— ↔,f ↔g,h ↑46 SD, ↑691 SD, ↓73 ↑755 SD, ↔ SD, ↑921,g ↓82 MD MD ↓88 MD ↓87 MD ↑735h CNS agents Buprenorphine/naloxone — — — ————— ↓14 ↑22 —— —— at ASPET Journals on September 28, 2021 Carbamazepine — ↓48 ——↓31 ↓70 ↓70 ↓87 ——— — ↓66 ↓51 Escitalopram ↓25 ——↔ ———— — — — — — — Methadone — ↑30 ————— ↔↑20 —— —— Other OC (norgestimate, norgestrel, — ↔↔— ↔e ↓34e ↓52e ↓29e ↔ —— — — — EE, or levonorgestrel)

CNS, central nervous system; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; EE, ethinyl estradiol; GLE, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; OC, oral contraceptive; PIB, pibrentasvir; PTV, paritaprevir; SD, single dose; /r, ritonavir; SMP, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir. ↑: increase in exposure; ↓: decrease in exposure; ↔: no change; —: data not available. aIndividualized dosing. b600 mg cyclosporine. cDepends on staggering of acid-reducing agent. d400 mg cyclosporine. eEE/norgestimate. f600 mg rifampin orally daily. g600 mg rifampin intravenously SD. h600 mg rifampin orally SD.

Carbamazepine was used to assess the sensitivity of ombitasvir/ DAAs as Victims of Metabolic and/or Transport Inhibitors. paritaprevir/ritonavir plus dasabuvir to induction. Coadministration Coadministration of DAAs with inhibitors of enzymes or transporters resulted in lower exposures for all agents (AUC and Cmax values may alter the disposition of DAAs. Several clinical studies evaluated were 30% and 31% lower for ombitasvir, 70% and 66% lower for DAAs as victims of metabolism- or transport-mediated interactions paritaprevir, 87% and 83% lower for ritonavir, and 70% and 55% using probe inhibitors. lower for dasabuvir, respectively) (Menon et al., 2015). Since Coadministration of a moderate CYP3A/P-gp inhibitor erythromycin marked reductions in exposure may result in a loss of antiviral with simeprevir (a substrate and an inhibitor of CYP3A/P-gp) resulted efficacy, the use of strong or moderate CYP3A inducers with in a clinically relevant two-way interaction. Briefly, simeprevir AUCt ombitasvir/paritaprevir/ritonavir plus dasabuvir is contraindicated and Cmax values were 647% and 353% higher, respectively; erythro- (Viekira Pak, 2017). mycin AUCt and Cmax values were 90% and 59% higher, respectively, Coadministration of elbasvir/grazoprevir, both CYP3A substrates, after coadministration (Ouwerkerk-Mahadevan et al., 2016; Olysio, with strong CYP3A inducers is contraindicated based on the expectation 2017). As such, the use of moderate or potent CYP3A inhibitors with that they will significantly decrease elbasvir and grazoprevir plasma simeprevir is not recommended (Olysio, 2017). Simeprevir is also a concentrations, leading to a reduced therapeutic effect (Viekirax, 2018; substrate of hepatic uptake transporter OATP1B1/3. Coadministration Zepatier, 2018). In the absence of definitive clinical data, coadministra- with inhibitors of OATP1B1/3, such as cyclosporine, may result in tion of elbasvir/grazoprevir with moderate CYP3A inducers is not higher simeprevir plasma concentrations and is not recommended recommended. (Olysio, 2017). 1216 Garrison et al.

TABLE 3 Impact of DAA on coadministered drug exposure (AUC) Data are given in percentages.

Drug Class SMP SOF LDV/SOF DCV OBV/PTV/DSV/r GZR EBR SOF/VEL SOF/VEL/VOX GLE/PIB Immunosuppressants Cyclosporine ↔↔↔ ↔ ↑482 ↔↔ — ↔ — Everolimus ——— — ↑2612 —— — — — Mycophenolic ——— — — ↔↔ —— — acid Sirolimus ——— — ↑3699 —— — — — Tacrolimus ↓17 ↔↔ ↔ ↑5613 ↑43 ↔ — ↑45 Statins Atorvastatin ↑112 —— — — ↑94 ↑54 — ↑728c Lovastatin ——— — —————↑70; lovastatin acid ↑310 Pravastatin ——— — ↑82 ↑33 ↑35 ↑116b ↑130c Rosuvastatin ↑181 —— ↑58 ↑159 ↑126 ↑169 ↑639b ↑115c Simvastatin ↑51; —— — ————— ↑132; simvastatin simvastatin acid

acid ↑88 ↑348 Downloaded from Cardiovascular Amiodaronea ——— — ————— — Amlodipine ——— — ↑157 —— — — — Dabigatran ——— — ————↑161b ↑138 Digoxin ↑39 —— ↔↑16 — ↔↑34 — ↑48c ——— — ————— ↑31 Losartan ——— — —————↑56; losartan ↔ acid dmd.aspetjournals.org Valsartan ——— — ————— ↑31 Antifungals — Ketoconazole ——— — ↑ 117 ———— Acid-reducing agents Omeprazole ↑21 —— — ↓38 —— — — ↓21 Antibacterial agents — Erythromycin ↑90 —— — ————— — Rifampin ↔ —— — —— —— — CNS agents — at ASPET Journals on September 28, 2021 Buprenorphine ——— ↑37 ↑107 ↔↔ —— — buprenorphine; buprenorphine; ↑62 ↑84 norbuprenorphine norbuprenorphine Hydrocodone ——— — ↑90 —— — — — Methadone ↔ —— ↔ — ↔↔ —— — Midazolam p.o. ↑45; —— — —↔ —— — ↑27 i.v. ↔ Other OC (NGMN, ↔↔EE; ↔ ↑20 EE; ↔ ↔↔EE; ↑160 ↔ ↔EE, ↔↔↑28–40 EE; ↑44 norgestimate, NGMN; NGMN; ↔ NGMN; ↑154 NG EE, LNG NGMN; ↑63–68 EE, or LNG) ↑19 NG NG LNG NG

CNS, central nervous system; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; LNG, levonorgestrel; NG, norgestrel; NGMN, ; OBV, ombitasvir; OC, oral contraceptive; PIB, pibrentasvir; PTV, paritaprevir; SMP, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir. ↑: increase in exposure; ↓: decrease in exposure; ↔: no change; —: data not available. aInteractions with amiodarone not identified although adverse events have been observed during coadministration with DAAs. bSOF/VEL/VOX plus VOX. c400/120 mg GLE/PIB daily.

DDI liability for sofosbuvir and ledipasvir (both P-gp/BCRP on ketoconazole-mediated CYP3A/P-gp inhibition, velpatasvir substrates) is limited to transporters. Coadministration of sofosbuvir AUC and Cmax values were 70% and 29% higher, respectively, with a potent P-gp/BCRP inhibitor cyclosporine (600 mg) increased the after coadministration (Mogalian et al., 2016b). Coadministration of sofosbuvir AUC and Cmax by 353% and 154%, respectively, without an velpatasvir with OATP1B inhibitor rifampin (single dose) resulted alteration in the GS-331007 AUC. Of note, at clinically relevant doses of in a modest (46%) increase in the velpatasvir AUC (Epclusa, cyclosporin, sofosbuvir exposure was minimally altered (AUC 15% 2017b). higher) with cyclosporine-based immunosuppressant regimens in post- Increases in sofosbuvir, ledipasvir, and velpatasvir pharmacoki- transplant patients (Kirby et al., 2015). The effect of transporter netics were not deemed clinically relevant and the use of P450 and inhibition on the pharmacokinetics of ledipasvir was assessed after drug transport inhibitors was permitted in the phase III sofosbuvir, coadministration of ledipasvir and the P-gp/OATP inhibitor atazanavir ledipasvir/sofosbuvir, and sofosbuvir/velpatasvir clinical programs. (ATV) plus ritonavir, resulting in a higher ledipasvir AUC (96%) and As reflected in the prescribing information, sofosbuvir, ledipasvir/ Cmax (68%) (German et al., 2015; Harvoni, 2017b). sofosbuvir, or sofosbuvir/velpatasvir may be used with P450, P-gp, Velpatasvir is metabolized by CYP3A and is a substrate for BCRP, and/or OATP inhibitors (Epclusa, 2017b; Harvoni, 2017b; several drug transporters, including P-gp, BCRP, and OATP. Based Sovaldi, 2017a). The DDI Potential of HCV DAAs 1217

TABLE 4 Impact of HIV coadministered HIV drug or regiment on DAA exposure (AUC) Data are given in percentages.

LDV/SOF OBV/PTV/DSV/r GZR/EBR SOF/VEL SOF/VEL/VOX GLE/PIB ARV Agent SMP SOF DCV LDV SOF OBV PTV DSV /r GZR EBR SOF VEL VOX GLE PIB NRTI ABC/3TC ———↔↔ ↔ ↓16 ↔ ———— — —— TDF ↔↔↔↔↔ —— ——↓14 ↔ — ↔↔—— Protease inhibitor (boosted) ATV/r ——↓30 —— ↔↑216 ↔↑218 ↑958 ↑376 —— ↑331 —— DRV/r ↑159 ↑34 ↓30 ↑39 ↑34 ↔,a ↑29,a ↓41,b ↔,a ↓27,b ↔,a ↑28,b ↑650 ↑66 —— — ↑397 ↔ ↓27,b ↔c ↓19c ↓28c ↑70c LPV/r ——↓42 —— ↔↑117 (↑87) ↔ (↓46) ↑105 ↑1186 ↑271 —— — ↑338 ↑146 (↑162) Entry/integrase inhibitor (unboosted) DTG ——↔ —— ↔↓16 ↔↓19 ↔↔↔ ——— RAL ↔↔— ↔↔ —— ——↔↓19 — ↔ ——— Downloaded from Non-NRTI EFV ↓71 — ↑37 ——————↓83 ↓54 —— — — — RPV ↔↔——— ↔↑23 ↔↔↔↔— ↔ ——— Pharmacokinetic enhancers (boosters) RTV ↑618 ————————↑103 ——— — — — Full treatment regimens ATV + RTV + ———↑96 ↔ —— ————↔↑142 ——— dmd.aspetjournals.org FTC/TDF BIC/FTC/TAF ———↔↔ —— ——————↔ —— DRV + RTV + ———↔↓27 —— ————↓28 ↔↑143 —— FTC/TDF DTG + FTC/TDF ———↔↔ —— ————————— EFV /FTC/TDF — ↔ — ↓34 ↔ —— ————↔↓53 ——— EVG/COBI/FTC/TAF ———↑79 ↑47 —— ——↑436 ↑118 ↑37 ↑50 ↑171 ↑105 ↑57 EVG/COBI/FTC/TDF ————— — — — — — —↔↔ ——— LPV/RTV + FTC/TDF ————— — — — — — —↓29 ↔ ——— RPV/FTC/TAF ————— — — — — — ——— ↔ —— at ASPET Journals on September 28, 2021 RPV/FTC/TDF ———↔↔ —— ————↔↔ ———

BIC, bictegravir; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; RTV or/r, ritonavir; SMP, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir. ↑: increase in exposure; ↓: decrease in exposure; ↔: no change; —: data not available. a800 mg DRV daily AM plus OBV/PTV/DSV/r AM versus 800 mg daily DRV AM plus 100 mg RTV daily AM. b600 mg DRV twice daily AM/PM plus OBV/PTV/DSV/r AM plus 100 mg RTV daily PM versus 600 mg DRV twice daily AM/PM plus 100 mg RTV twice daily AM/PM. cOBV/PTV/DSV/r AM plus 800 mg DRV daily PM plus 100 mg RTV daily PM versus 800 mg DRV daily PM plus 100 mg RTV daily PM.

Slow turnover of voxilaprevir, primarily by CYP3A, has been ketoconazole (AUC 117%; Cmax 15%). Ketoconazole did not alter observed and voxilaprevir is also a substrate for several drug trans- ombitasvir pharmacokinetics, in which P-gp play a role (Menon et al., porters, including P-gp, BCRP, and OATP1B1/3. Voriconazole- 2015). Based on these collective data, the maximum daily dose of mediated CYP3A inhibition resulted in an 84% higher voxilaprevir ketoconazole should be limited to 200 mg/day during coadministration AUC, with no change in Cmax (Kirby et al., 2016a). Coadministration of with ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak, voxilaprevir with combined P-gp/BCRP/OATP inhibitor cyclosporine 2017). (600 mg) resulted in 840% and 1800% higher AUC and Cmax, Dasabuvir is primarily metabolized by CYP2C8. Administration respectively, where the majority of the effect was attributed to OATP of dasabuvir with potent CYP2C8 inhibitor gemfibrozil resulted in a inhibition based on the results of coadministration of voxilaprevir higher dasabuvir AUC (1025%) and Cmax (101%), respectively. Higher with the OATP1B inhibitor rifampin (single dose; 691% and 1010% dasabuvir exposures were associated with QT prolongation; thus, use of higher AUC and Cmax, respectively) (Kirby et al., 2016a). Coadminis- strong inhibitors of CYP2C8 with ombitasvir/paritaprevir/ritonavir plus tration of sofosbuvir/velpatasvir/voxilaprevir with cyclosporine is not dasabuvir is contraindicated (Viekira Pak, 2017). recommended. Elbasvir and grazoprevir are substrates of P-gp and CYP3A, and Consistent with the role of CYP3A and P-gp in daclatasvir grazoprevir is also a substrate of OATP1B1/3. Coadministration of pharmacokinetics, daclatasvir AUC and Cmax values were 200% and elbasvir/grazoprevir with P-gp inhibitors is expected to have minimal 57% higher, respectively, with ketoconazole (Daklinza, 2017). A dose effect, because the role of intestinal P-gp on the absorption of elbasvir reduction to 30 mg daclatasvir is recommended with strong CYP3A and grazoprevir appears to be minimal (Zepatier, 2018). Coadministra- inhibitors. Monitoring for daclatasvir adverse events is recommended if tion of elbasvir/grazoprevir with ketoconazole resulted in higher AUC daclatasvir is coadministered with moderate CYP3A inhibitors (Eley and Cmax values for elbasvir (80% and 29%, respectively) and et al., 2014; Daklinza, 2017, 2018). grazoprevir (202% and 13%, respectively) (Zepatier, 2018). The use A two-way interaction was observed between ombitasvir/paritapre- of strong CYP3A inhibitors with elbasvir/grazoprevir is not recom- vir/ritonavir plus dasabuvir and ketoconazole, as evidenced by higher mended. Coadministration of elbasvir/grazoprevir and cyclosporine plasma exposures of paritaprevir (AUC 98%; Cmax 37%), ritonavir (400 mg) resulted in higher AUC and Cmax values for elbasvir (AUC 57%; Cmax 27%), dasabuvir (AUC 42%; Cmax 16%), and (98% and 95%, respectively) and grazoprevir (1421% and 1600%, 1218 Garrison et al.

TABLE 5 Impact of DAA on coadministered HIV drug exposure (AUC) Data are given in percentages.

GZR/EBR ARV Agent SMP SOF DCV LDV/SOF OBV/PTV/DSV/r SOF/VEL SOF/VEL/VOX GLE/PIB GZR EBR NRTI ABC ——— ↔↔—— — — ↔b FTC — ↔ — ↔ — ↔b ↔b ↔b — 3TC ——— — — — — — — TAF (10 mg, boosted) ——— ↔b,d ———↔b,d ↔b,d ↔b,d TAF (25 mg, nonboosted) ——— — — — — — ↑52–57b — TDF (boosted regimen) ———↔, ↑50b,c — ↔b,d ↔, ↑39b,c ↑39b,c — TDF (nonboosted regimen) ↔a ↔b — ↑98a — ↔a ↑40–↑81b — ↔b Protease inhibitor ATV ——— ↔b,c ↔a,c ↑43a,c ↔a,c ↔b,c —— DRV ↔a,c ↔↔a,c ↔b,c ↓24,a,e ↔,a,f ↑34a,g ↔a,c,h ↔a,c,h ↔b,c ↔b,c ↔b,c LPV ——↔a,c — ↔a,c ↔a,c ↔a,c ↔i —— Entry/integrase inhibitor BIC — ↔b ————↔b — Downloaded from DTG ——↑33a ↔↑38 ↔a ↔ —— EVG ——— ↔b,d — ↔b ↔b,d ↔b,d ↔b,d RAL ↔a ↔ — ↔ — ↑43d ↔a ↔b — ↑47a Non-NRTI EFV (600 mg daily) ↔a ↔ — ↔ — ↔a ↔a ↔b —— RPV (25 mg daily) ↔a ↔ — ↔↑225a ↔a ↔b ↔b ↑84a Pharmacokinetic enhancers (boosters) COBI ——— ↑53 — ↑49 ↔b ↑50 — dmd.aspetjournals.org RTV ↔ —— ↔ ———↔b ↑45 ↑87

BIC, bictegravir; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; RTV or/r, ritonavir; SMP, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir. ↑: increase in exposure; ↓: decrease in exposure; ↔: no change; —: data not available. aHIV drug tested as a single agent. bHIV drug tested as part of antiretroviral therapy regimen. cBoosted with 100 mg RTV daily. dBoosted with 150 mg COBI daily. e800 mg DRV daily AM plus OBV/PTV/DSV/r AM versus 800 mg DRV daily AM plus 100 mg RTV daily AM. f600 mg DRV twice daily AM/PM plus OBV/PTV/DSV/r AM plus 100 mg RTV daily PM versus 600 mg DRV twice daily AM/PM plus 100 mg RTV twice daily AM/PM.

gOBV/PTV/DSV/r AM plus 800 mg DRV daily PM plus 100 mg RTV daily PM versus 800 mg DRV daily PM plus 100 mg RTV daily PM. at ASPET Journals on September 28, 2021 h600/100 mg twice daily. i800/200 mg daily.

respectively), due to inhibition of P-gp, OATP1B1/3, and CYP3A Sofosbuvir, ledipasvir, velpatasvir, and elbasvir are not expected to (Zepatier, 2018). Coadministration of OATP1B1/3 inhibitors with perpetrate any metabolic enzyme-mediated DDIs. Although daclatasvir grazoprevir/elbasvir is contraindicated due to significantly higher may induce CYP3A, several clinical studies with coadministered grazoprevir concentrations. CYP3A substrates have demonstrated that daclatasvir is unlikely to Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP, and elicit clinically relevant interactions (Garimella et al., 2016). glecaprevir is also a substrate of OATP1B1/3. Coadministration of P-gp The exposure of omeprazole, a substrate of CYP2C19, was 38% and BCRP inhibitors may increase glecaprevir and pibrentasvir plasma lower when coadministered with ombitasvir/paritaprevir/ritonavir plus exposures, whereas coadministration of OATP1B1/3 inhibitors will dasabuvir, revealing an inductive effect of the DAA regimen on increase glecaprevir plasma exposures. Coadministration of cyclospor- CYP2C19 and possibly warranting adjustment of the omeprazole dose ine (400 mg), an inhibitor of P-gp/BCRP/OATP1B, resulted in a higher in patients whose symptoms are poorly controlled (Menon et al., 2015). glecaprevir AUC (408%) and Cmax (351%) and a higher pibrentasvir Use of sensitive CYP3A substrates with ombitasvir/paritaprevir/ritona- AUC (93%) with no change in Cmax (Mavyret, 2017; Maviret, 2018). vir plus dasabuvir is contraindicated due to the presence of potent Coadministration of single-dose rifampin, an OATP1B inhibitor, CYP3A inhibitor ritonavir within the regimen (Viekira Pak, 2017). resulted in a higher glecaprevir AUC (755%) and Cmax (552%) with Ombitasvir, paritaprevir, and dasabuvir are also inhibitors of UGT1A1 no change in pibrentasvir exposure (Mavyret, 2017; Maviret, 2018). and may result in higher plasma concentrations of drugs that are Regional prescribing information for glecaprevir/pibrentasvir should be UGT1A1 substrates (e.g., ; see label) (Viekira Pak, 2017). consulted for specific recommendations on the coadministration of various P-gp, BCRP, and/or OATP1B inhibitors (Mavyret, 2017; Transporter-Mediated Interactions Maviret, 2018). P-gp (Digoxin or Dabigatran Etexilate as Probe Substrates). DAAs as Perpetrators Metabolizing Enzyme-Mediated Interac- Digoxin and dabigatran etexilate are P-gp substrates that help to assess tions. The potential of simeprevir to perpetrate P450-mediated DDIs P-gp–mediated DDIs. Dabigatran etexilate is primarily sensitive to P-gp was evaluated using a metabolic cocktail approach. Simeprevir demon- intestinally, and digoxin is sensitive to P-gp both intestinally and strated mild inhibition of CYP1A2 (caffeine AUC 26% higher) and systemically. Overall digoxin exposure (AUC) was modestly higher intestinal CYP3A (oral midazolam AUC 45% higher; Cmax 31% higher) after coadministration with simeprevir, daclatasvir, ledipasvir, or with no alteration in exposure after intravenous midazolam (Sekar et al., velpatasvir (AUC 27%–34% higher) and was 11% higher with elbasvir 2010). No effect on CYP2C9, CYP2C19, or CYP2D6 was observed (Eley et al., 2011; German et al., 2014b; Mogalian et al., 2016b; (Olysio, 2017). Ouwerkerk-Mahadevan et al., 2016; Daklinza, 2017; Zepatier, 2018). The DDI Potential of HCV DAAs 1219

Administration of digoxin with ombitasvir/paritaprevir/ritonavir plus Numerous studies were conducted on the coadministration of dasabuvir resulted in no alteration to digoxin exposure despite in vitro glecaprevir/pibrentasvir with statins. Coadministration of glecaprevir/ P-gp inhibition by ritonavir, paritaprevir, and dasabuvir (Menon et al., pibrentasvir resulted in higher exposures for atorvastatin (AUC 728%; 2015). Due to the narrow therapeutic index of digoxin, caution is Cmax 2100%), simvastatin (AUC 132%; Cmax 99%; simvastatin acid warranted and therapeutic monitoring may be required during co- AUC 348%; Cmax 970%), lovastatin (AUC 70%; lovastatin acid administration with simeprevir, daclatasvir, ledipasvir/sofosbuvir, or AUC 310%; Cmax 473%), pravastatin (AUC 130%; Cmax 123%), and sofosbuvir/velpatasvir. Per the prescribing information, no dose adjust- rosuvastatin (AUC 115%; Cmax 462%). Coadministration of atorvas- ment for digoxin is required for coadministration with ombitasvir/ tatin, lovastatin, and simvastatin with glecaprevir/pibrentasvir is not paritaprevir/ritonavir plus dasabuvir or elbasvir/grazoprevir (Viekira recommended. If glecaprevir/pibrentasvir is coadministered with Pak, 2017; Zepatier, 2018). pravastatin, the pravastatin dose should be reduced by 50%. The Dabigatran exposure (AUC) was 161% higher after coadminis- rosuvastatin dose should not exceed 10 mg when coadministered with tration with sofosbuvir/velpatasvir/voxilaprevir and was 138% higher glecaprevir/pibrentasvir. upon coadministration with glecaprevir/pibrentasvir (Mavyret, 2017; In summary, caution and appropriate monitoring for statin-, digoxin-, Vosevi, 2017a,b; Maviret, 2018). Regional prescribing information for or dabigatran-related adverse events has been recommended for DAAs sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir should identified or expected to cause transporter (or CYP3A)–mediated be consulted for specific recommendations on coadministration with interactions. In specific cases, coadministration is not recommended or dabigatran etexilate. dosing recommendations are specified within the prescribing informa- Downloaded from OATP1B and BCRP (Pravastatin and Rosuvastatin as Probe tion. These data also inform potential for interactions with other sensitive Substrates). 3-Hydroxy-3-methylglutaryl–CoA reductase inhibitors substrates of these drug transporters. (statins) are commonly used as probes to assess OATP- and/or BCRP- mediated DDIs clinically. The hepatic uptake of most statins, including Other Commonly Used Medications in HCV pravastatin and rosuvastatin, is mediated by OATP1B1 (Neuvonen Methadone and Buprenorphine et al., 2006). Rosuvastatin is also transported by BCRP (and sodium- taurocholate cotransporting polypeptide) (Neuvonen et al., 2006). Opioid agonists, methadone and buprenorphine, are frequently pre- dmd.aspetjournals.org Rosuvastatin exposure was higher after administration with simepre- scribed in the HCV-infected population to treat opioid dependence. No vir (AUC 181%; Cmax 217%) and with daclatasvir (AUC 58%; Cmax clinically meaningful interactions were observed when simeprevir, 104%) due to inhibition of OATP and BCRP (Daklinza, 2014, 2017; sofosbuvir, daclatasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, Olysio, 2017). Caution and appropriate monitoring for statin-related elbasvir/grazoprevir, or glecaprevir/pibrentasvir were administered to adverse events is recommended on coadministration of rosuvastatin with patients receiving opioid therapy with methadone (CYP3A and simeprevir or daclatasvir; for simeprevir, the dose of rosuvastatin should CYP2B6 substrate), whereas daclatasvir or elbasvir/grazoprevir did be initiated at 5 mg once daily and should not exceed 10 mg once daily not impact the pharmacokinetics of buprenorphine (CYP3A and at ASPET Journals on September 28, 2021 (Olysio, 2017). CYP2C8 substrate) (Daklinza, 2017; Olysio, 2017; Sovaldi, 2017a; OATP- and BCRP-associated DDI liabilities were not directly Viekira Pak, 2017; Zepatier, 2018). Ledipasvir/sofosbuvir, sofosbuvir/ assessed for ledipasvir. In the absence of definitive clinical data, the velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir do not inhibit or use of rosuvastatin with ledipasvir/sofosbuvir is not recommended induce enzymes involved in the disposition of methadone or buprenor- (Harvoni, 2017a). Pravastatin can be used with ledipasvir/sofosbuvir phine; thus, DDI studies with these agents were not conducted. without dose modification (Harvoni, 2017b). Administration of velpa- Coadministration of ombitasvir/paritaprevir/ritonavir plus dasabuvir tasvir resulted in higher AUC and Cmax values for pravastatin (35% and resulted in higher AUC and Cmax values for buprenorphine (107% and 28%, respectively) and rosuvastatin (169% and 161%, respectively). 118%, respectively) and norbuprenorphine (major active metabolite; Pravastatin can be used without dose modification and the dose of 84% and 107%, respectively) (Menon et al., 2015). Although no rosuvastatin should not exceed 10 mg once daily when coadministered buprenorphine dose adjustment is necessary, close monitoring of with sofosbuvir/velpatasvir (Mogalian et al., 2016b). patients for sedation and cognitive effects during coadministration with With ombitasvir/paritaprevir/ritonavir plus dasabuvir, coadministered ombitasvir/paritaprevir/ritonavir plus dasabuvir is warranted (Viekira pravastatin resulted in higher pravastatin AUC (82%) and Cmax (37%), Pak, 2017). and coadministered rosuvastatin resulted in higher rosuvastatin AUC Immunosuppressants (159%) and Cmax (613%) (Viekira Pak, 2017). The daily doses of pravastatin and rosuvastatin should not exceed 40 and 10 mg, re- Recurrence of HCV infection is universal in viremic patients after spectively, when administered with ombitasvir/paritaprevir/ritonavir liver transplantation, and treatment of HCV infection in post-transplant plus dasabuvir (Viekira Pak, 2017). patients is associated with substantial improvements in both patient and Coadministration of elbasvir/grazoprevir with pravastatin resulted in graft survival (Suraweera et al., 2016). inhibitors tacrolimus no clinically relevant change to pravastatin AUC (33% higher) or Cmax and cyclosporine are commonly used to prevent graft rejection. (28% higher), whereas coadministration with rosuvastatin resulted in Cyclosporine. Cyclosporine is a substrate of CYP3A, P-gp, and higher rosuvastatin AUC (126%) and Cmax (449%) (Zepatier, 2018). OATP1B and a strong inhibitor of CYP3A, P-gp, BCRP, and OATP1B The rosuvastatin dose should not exceed 10 mg once daily when (Prograf, 2003; Krishna et al., 2007; Kalliokoski and Niemi, 2009; coadministered with elbasvir/grazoprevir (Zepatier, 2018). Neoral, 2009). A wide range of cyclosporine doses were used to assess Coadministration of sofosbuvir/velpatasvir/voxilaprevir with prava- DDI susceptibility with DAAs, ranging from low doses (30 mg) or statin resulted in higher pravastatin AUC (116%) and Cmax (89%), higher doses (up to 600 mg) that are more typical of doses after organ whereas coadministration with rosuvastatin resulted in higher rosuvas- transplantation. tatin AUC (639%) and Cmax (1788%) (Vosevi, 2017a,b). The daily dose Higher cyclosporine AUC (19%) and Cmax (16%) was observed after of pravastatin should not exceed 40 mg when administered with coadministration of cyclosporine (400 mg) with simeprevir (Ouwerkerk- sofosbuvir/velpatasvir/voxilaprevir, whereas rosuvastatin should not Mahadevan et al., 2012c). Results from a phase II study of simeprevir in be coadministered. combination with daclatasvir and ribavirin in HCV-infected post–liver 1220 Garrison et al. transplant patients showed higher simeprevir AUC (468%) and Cmax with sofosbuvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/ (353%) with cyclosporine (Ouwerkerk-Mahadevan et al., 2016; Olysio, velpatasvir/voxilaprevir, or daclatasvir (Epclusa, 2017b; Harvoni, 2017b; 2017); coadministration of cyclosporine and simeprevir is not recom- Sovaldi, 2017a; Vosevi, 2017a). mended due to the significantly higher simeprevir exposure (Olysio, Tacrolimus AUC and Cmax values were 5613% and 299% higher, 2017). respectively, when administered with ombitasvir/paritaprevir/ritonavir Cyclosporine (600 mg)–mediated inhibition of P-gp/BCRP resulted plus dasabuvir (Badri et al., 2015; Viekira Pak, 2017); the effect of in higher sofosbuvir AUC (353%) and Cmax (154%) values without ombitasvir/paritaprevir/ritonavir plus dasabuvir on tacrolimus pharma- altering GS-331007 exposure; no sofosbuvir dose adjustment is required cokinetics is consistent with strong CYP3A inhibition by ritonavir. during use with cyclosporine (Mathias et al., 2012). Similarly, no dose Based on these data, the use of tacrolimus (as well as sirolimus and adjustment is required for ledipasvir or velpatasvir (AUC 103% higher; everolimus) is contraindicated with ombitasvir/paritaprevir/ritonavir Cmax 56% higher) when coadministered with cyclosporine (Mogalian plus dasabuvir (Viekira Pak, 2017; Viekirax, 2018). et al., 2016b). Cyclosporine may be administered with sofosbuvir, The tacrolimus AUC was 43% higher when coadministered with ledipasvir/sofosbuvir, or sofosbuvir/velpatasvir. As discussed above, grazoprevir, thus warranting the monitoring of tacrolimus concentra- the strong inhibition of OATP1B by cyclosporine (600 mg) was tions, adverse events, and changes in renal function upon initiation of primarily responsible for the higher voxilaprevir AUC (839%) and Cmax coadministration with elbasvir/grazoprevir (Zepatier, 2018). (1802%) observed after coadministration with sofosbuvir/velpatasvir/ Coadministration of glecaprevir/pibrentasvir with tacrolimus resulted voxilaprevir. Coadministration of cyclosporine with sofosbuvir/ in a higher tacrolimus AUC (45%) and Cmax (50%). In association with Downloaded from velpatasvir/voxilaprevir is not recommended (Vosevi, 2017a). the expected increase in tacrolimus exposure, use with caution and A higher daclatasvir AUC (40%) was observed with cyclosporine therapeutic monitoring (including dose adjustment) of tacrolimus is (400 mg), with no change in cyclosporine pharmacokinetics, supporting recommended upon coadministration with glecaprevir/pibrentasvir coadministration of cyclosporine with daclatasvir (Bifano et al., 2013). (Mavyret, 2017). The cyclosporine AUC was 482% higher with no alteration in Cmax when administered with ombitasvir/paritaprevir/ritonavir plus dasabuvir Oral Contraceptives (Badri et al., 2015; Viekira Pak, 2017). The effect of ombitasvir/ Commonly used oral hormonal contraceptives contain a combination dmd.aspetjournals.org paritaprevir/ritonavir plus dasabuvir on cyclosporine pharmacokinetics of (e.g., ethinyl estradiol; EE) and progestins (e.g., noreth- is consistent with OATP and CYP3A inhibition by paritaprevir and indrone, norgestimate, or levonorgestrel) that undergo extensive me- ritonavir, respectively. Based on these results, specific dosing recom- tabolism. EE is a substrate for P-gp/BCRP, CYP3A, UGT, and mendations were warranted and are discussed in more detail in the USPI sulfotransferase (Zhang et al., 2007). Norgestimate undergoes first- and SmPC (Viekira Pak, 2017; Viekirax, 2018). The effects of low-dose pass metabolism to the primary active metabolite norelgestromin and is (30 mg) cyclosporine on ombitasvir/paritaprevir/ritonavir plus dasabuvir then metabolized to norgestrel, which has limited biologic activity, and pharmacokinetics resulted in higher paritaprevir AUC (72%), lower other metabolites (Hammond et al., 2003; Olysio, 2017). HCV-infected at ASPET Journals on September 28, 2021 dasabuvir AUC (30%), and no change in the exposure of ombitasvir or women of childbearing potential may need to receive ribavirin ritonavir. ( category X) with their DAA regimen, thus warranting As discussed above, coadministration of elbasvir/grazoprevir with assessment of DDIs between DAAs and oral contraceptives. cyclosporine is contraindicated due to significantly higher simeprevir Results from DDI studies demonstrated no need for dose adjustment AUC (1421%) and Cmax (1600%) after administration with cyclosporine of evaluated oral contraceptives with simeprevir, sofosbuvir, ledipasvir/ 400 mg (Zepatier, 2018). sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, Coadministration of glecaprevir/pibrentasvir with two different doses daclatasvir, elbasvir/grazoprevir, or glecaprevir/pibrentasvir. Briefly, of cyclosporine (100 or 400 mg) was studied. At the higher cyclosporine administration of simeprevir with EE/norethindrone increased EE Cmax dose, coadministration resulted in higher glecaprevir AUC (408%) and (18%), with no alteration to other parameters (Ouwerkerk-Mahadevan Cmax (351%) and higher pibrentasvir AUC (93%) with no change in et al., 2012d). Coadministration of sofosbuvir, ledipasvir, or velpatasvir Cmax (Mavyret, 2017; Maviret, 2018). At the lower cyclosporine dose, with EE/norgestimate resulted in a higher norgestrel AUC (19%) with the glecaprevir AUC was 37% higher (Cmax 30% higher), with no sofosbuvir or a higher EE Cmax with ledipasvir (40%) or velpatasvir change in pibrentasvir exposure. Coadministration of glecaprevir/ (39%), respectively (German et al., 2014a). EE Cmax increases with pibrentasvir with stable cyclosporine doses .100 mg/day is not ledipasvir or velpatasvir were attributed to P-gp/BCRP inhibition; a recommended (Mavyret, 2017). mechanism for higher norgestrel AUC with sofosbuvir is unknown Tacrolimus. Tacrolimus is a substrate of CYP3A and P-gp, although (German et al., 2014a; Mogalian et al., 2014). There was no alteration in it is more sensitive to P450-mediated drug interactions (Prograf, 2003; EE or norgestimate pharmacokinetics with sofosbuvir/velpatasvir/ Krishna et al., 2007; Kalliokoski and Niemi, 2009; Neoral, 2009). voxilaprevir (Vosevi, 2017a). Daclatasvir or elbasvir/grazoprevir did Tacrolimus is also an inhibitor of CYP3A and P-gp. not alter pharmacokinetics of EE/norgestimate or EE/levonorgestrel, No alteration in tacrolimus exposure was observed after coadminis- respectively (Bifano et al., 2014; Daklinza, 2017; Marshall et al., 2017; tration with simeprevir (Ouwerkerk-Mahadevan et al., 2012c). Results Zepatier, 2018). Coadministration of glecaprevir/pibrentasvir with from a phase II study of simeprevir in combination with and ribavirin in EE/nogestimate or EE/levonorgestrel resulted in higher EE (28%– HCV-infected post–liver transplant patients showed higher simeprevir 40%), norgestrel (63%–68%), and/or norelgestromin (44%). No dose AUC (90%) and Cmax (85%) with tacrolimus; no dose adjustment is adjustment with levonorgestrel, norethnidrone, or norgestimate is required when simeprevir is administered with tacrolimus (Ouwerkerk- needed when coadministered with glecaprevir/pibrentasvir; coadmin- Mahadevan et al., 2016; Olysio, 2017). istration of glecaprevir/pibrentasvir is contraindicated with EE- No clinically relevant interactions were observed between tacrolimus containing oral contraceptives due to risk of alanine aminotransferase and sofosbuvir or daclatasvir (Bifano et al., 2013; Daklinza, 2017). (ALT) elevations. Based on the DDI profiles for ledipasvir, velpatasvir, voxilaprevir, and Administration of ombitasvir/paritaprevir/ritonavir plus dasabuvir tacrolimus, clinically significant interactions are not expected and thus with EE/norgestimate did not significantly impact EE but resulted in the DDI studies were not conducted. Tacrolimus may be administered higher norelgestromin AUC (160%) and norgestrel AUC (154%) and The DDI Potential of HCV DAAs 1221 lower paritaprevir AUC (34%), ritonavir AUC (29%), and dasabuvir regimens are due to comparatively lower TFV exposure when AUC (52%) (Menon et al., 2015). The use of EE-containing oral administered as EFV/FTC/TDF, which is recommended to be given contraceptives with ombitasvir/paritaprevir/ritonavir plus dasabuvir on an empty stomach. The addition of voxilaprevir (i.e., sofosbuvir/ is contraindicated due to potential for ALT elevations during co- velpatasvir/voxilaprevir) did not further impact TFV exposures com- administration; the mechanism for this pharmacodynamic interaction pared with those observed with sofosbuvir/velpatasvir (39% higher is unknown (Menon et al., 2015). Coadministration of ombitasvir/ AUC with DRV/r plus FTC/TDF; Vosevi, 2017a,b). The mechanism for paritaprevir/ritonavir plus dasabuvir with norethindrone (progestin-only the higher TFV exposure from TDF-containing regimens is attributed to contraceptive) resulted in altered exposure for only paritaprevir (AUC inhibition of P-gp/BCRP by ledipasvir or velpatasvir and/or voxilaprevir. 23% higher), supporting coadministration (Viekira Pak, 2017; Viekirax, Monitoring for TFV-associated adverse events in patients receiving 2018). ledipasvir/sofosbuvir or sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/ voxilaprevir with an ARV regimen containing TDF is advised (Epclusa, HCV/HIV Coinfection 2017b; Harvoni, 2017b; Vosevi, 2017a). Administration of ombitasvir/paritaprevir/ritonavir plus dasabuvir Approximately 25% of HIV-infected individuals in the United States with FTC/TDF resulted in lower paritaprevir AUC (16%) and Cmax are coinfected with HCV (Soriano et al., 2010; https://www.cdc.gov/ (32%) with no other relevant interactions (Khatri et al., 2014a); no dose hepatitis/populations/hiv.htm and https://www.cdc.gov/hepatitis/ adjustment of FTC/TDF is needed. No clinically significant interactions hepawarenessabcs.htm). Liver fibrosis progresses approximately three were observed with ombitasvir/paritaprevir/ritonavir plus dasabuvir Downloaded from times more rapidly in HIV/HCV-coinfected patients than in patients with administered with ABC/3TC (Khatri et al., 2016). HCV monoinfection (Graham et al., 2001). Although current guidelines The regimen-based approach was used to assess DDIs between for ARV therapy in patients with HIV are the same regardless of HCV glecaprevir/pibrentasvir and FTC-, TDF-, and TAF-containing regi- coinfection status, the selection of HCV DAAs must be carefully mens. The TFV AUC was unchanged after coadministration of considered due to the potential for significant DDIs between treatment glecaprevir/pibrentasvir with elvitegravir (EVG)/cobicistat (COBI)/ regimens. An important consideration in evaluating results of DDI FTC/TAF and was 29% higher after coadministration of glecaprevir/ studies between HCV DAAs and HIV ARVs is whether those studies pibrentasvir with EFV/FTC/TDF (Mavyret, 2017; Maviret, 2018). dmd.aspetjournals.org were conducted with full treatment regimens or with only single components, as studies accounting for both intra- and inter-regimen Non-NRTIs DDIs best advise the possible magnitude, and thus clinical interpretation, Non-NRTIs EFV and RPV are approved for use in combination with of DDI results. two NRTIs for the treatment of HIV (https://aidsinfo.nih.gov/guidelines/ html/1/adult-and-adolescent-arv/11/what-to-start). Nucleoside/Nucleotide Reverse Transcriptase Inhibitors Efavirenz. EFV is a CYP2B6 and CYP3A substrate and has also

Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), been shown to induce hepatic CYP2B6 and CYP3A, and as such may at ASPET Journals on September 28, 2021 such as tenofovir disoproxil fumarate (TDF), tenofovir alafenamide decrease the exposure of drugs metabolized by these enzymes (Olysio, (TAF), emtricitabine (FTC), abacavir (ABC), and lamivudine (3TC) 2017; Sustiva, 2017). Consistent with EFV-mediated CYP3A induction, are considered the backbones of HIV treatment regimens. Tenofovir lower plasma exposure of simeprevir (AUC 71% lower) was observed disoproxil and TAF are both P-gp/BCRP substrates and prodrugs of the after coadministration of EFV single agent (Ouwerkerk-Mahadevan nucleotide analog tenofovir (TFV) (Tong et al., 2007). FTC, ABC, and et al., 2012a). A decrease in the velpatasvir AUC (53%) was also 3TC are known to have a limited DDI profile. TFV, FTC, and 3TC are observed after coadministration of sofosbuvir/velpatasvir with renally eliminated (Epivir, 2013; Truvada, 2017). EFV/FTC/TDF, although no impact of sofosbuvir AUC was observed Results of DDI studies between TDF (single agent) and simeprevir, (Mogalian et al., 2015a). Due to a potential loss of therapeutic effect, daclatasvir, or elbasvir/grazoprevir did not demonstrate clinically coadministration of simeprevir or sofosbuvir/velpatasvir with EFV- relevant interactions (i.e., ,30% increase in TFV exposure from based regimens is not recommended (Olysio, 2017). TDF), supporting use of these agents together (Bifano et al., 2012; Coadministration of ledipasvir/sofosbuvir with EFV/FTC/TDF Olysio, 2017; Zepatier, 2018). resulted in 34% lower ledipasvir AUC. The decrease was not deemed A regimen-based approach was used to assess DDIs between clinically relevant; the mechanism was postulated to be related to sofosbuvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/ induction of P-gp and/or oxidative pathways that mediate ledipasvir velpatasvir/voxilaprevir with boosted and unboosted FTC-, TDF-, and disposition. Again, no change in sofosbuvir pharmacokinetics was TAF-containing regimens. Administration with sofosbuvir, ledipasvir/ observed with EFV/FTC/TDF (German et al., 2014c). sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir EFV was predicted to lower daclatasvir exposure by 50%, but a did not result in clinically relevant interactions with FTC or TAF as part clinical study of 120 mg daclatasvir (twice the clinical dose) showed a of any regimen (Kirby et al., 2012; Epclusa, 2017b; Harvoni, 2017b; more modest decrease (approximately 30%) on daclatasvir exposure, Sovaldi, 2017a; Vosevi, 2017a). thereby supporting the use of daclatasvir 90 mg with EFV (Daklinza, Coadministration of ledipasvir/sofosbuvir with TDF-containing reg- 2017). imens resulted in higher TFV exposures from EFV/FTC/TDF (AUC Administration of elbasvir and grazoprevir with EFV resulted in 98% higher; Cmax 79% higher) and FTC/rilpivirine (RPV)/TDF (AUC significantly lower AUC for both elbasvir (54%) and grazoprevir (83%); 40% higher); similar increases in TFV exposure (approximately 40%) coadministration of elbasvir/grazoprevir with EFV-containing HIV were observed with other regimens, including ritonavir-boosted ATV or ARV regimens is contraindicated (Zepatier, 2018). The use of darunavir (DRV) plus FTC/TDF (Harvoni, 2017b). Coadministration of ombitasvir/paritaprevir/ritonavir plus dasabuvir with EFV-based regi- sofosbuvir/velpatasvir with boosted and unboosted TDF-containing mens is also contraindicated, as a DDI study with EFV/FTC/TDF regimens resulted in similar effects on TFV (approximately 40% higher resulted in premature study discontinuation due to significant gastroin- AUC and Cmax for all regimens except EFV/FTC/TDF; TFV AUC 81% testinal and neurologic adverse events and liver enzyme elevations higher) (Mogalian et al., 2015a, 2016a,c, 2018). The relatively larger (HCV Guidelines, 2015). No pharmacokinetic results are available from changes in TFV seen with EFV/FTC/TDF compared with other this study (Viekira Pak, 2017). 1222 Garrison et al.

Coadministration of glecaprevir/pibrentasvir with EFV/FTC/TDF due to ATV/r-mediated P-gp/BCRP inhibition. The sofosbuvir AUC resulted in significantly lower exposures of glecaprevir and pibrentasvir was unchanged when ledipasvir/sofosbuvir was administered with (exposure values not reported); coadministration of glecaprevir/ ATV/r plus FTC/TDF, likely due to existing P-gp/BCRP inhibition by pibrentasvir with EFV-containing regimens is not recommended ledipasvir as part of ledipasvir/sofosbuvir. ATV and ritonavir Cmin (Mavyret, 2017). values were 63% and 45% higher, respectively, when administered with Rilpivirine. RPV is a CYP3A substrate and does not perpetrate ledipasvir/sofosbuvir. Administration of ledipasvir/sofosbuvir with a transport- or enzyme-mediated interactions at the clinically relevant dose. DRV/r-based regimen resulted in modestly lower sofosbuvir AUC RPV is available as a single agent or within fixed-dose combinations (27%) and Cmax (37%) with no alteration in GS-331007, ledipasvir, FTC/RPV/TDF or FTC/RPV/TAF. DRV, or ritonavir AUC. For DAAs such as simeprevir, ledipasvir/sofosbuvir, sofosbuvir/ Administration of sofosbuvir/velpatasvir with FTC/TDF plus ATV/r, velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, daclatasvir, and elbasvir/ DRV/r, or LPV/r resulted in a higher velpatasvir AUC (142%) after grazoprevir that do not inhibit CYP3A, no clinically relevant interactions administration with ATV/r, attributable to P-gp/BCRP and CYP3A were observed in DDI studies, thereby supporting coadministration of these inhibition. No change in the velpatasvir AUC was observed when agents with RPV-containing regimens. administered with DRV/r or LPV/r. The overall exposure of ATV, DRV, DDIs between ombitasvir/paritaprevir/ritonavir plus dasabuvir and LPV, and ritonavir was unaffected after administration with sofosbuvir/ RPV were also assessed. Coadministration of RPV with ombitasvir/ velpatasvir, supporting coadministration of these regimens (Epclusa, paritaprevir/ritonavir plus dasabuvir did not alter the pharmacoki- 2017b). Downloaded from netics of ritonavir, ombitasvir, or dasabuvir, whereas higher paritap- Coadministration of sofosbuvir/velpatasvir/voxilaprevir with DRV revir AUC (23%) and Cmax (30%) were observed (Khatri et al., plus ritonavir plus FTC/TDF resulted in a higher voxilaprevir AUC 2014a). Significantly higher RPV AUC (225%) and Cmax (155%) were (143%) and Cmax (72%), supporting coadministration. Coadministration observed after administration of RPV with ombitasvir/paritaprevir/ of sofosbuvir/velpatasvir/voxilaprevir with a single dose of ATV/r ritonavir plus dasabuvir, attributable to CYP3A inhibition by resulted in a relatively greater effect (voxilaprevir AUC and Cmax values ritonavir. Since higher concentrations of RPV may cause QTc were 331% and 342% higher, respectively) due to comparatively more interval prolongation (Olysio, 2017), coadministration of ombitasvir/ potent OATP inhibition as well as P-gp/BCRP and CYP3A inhibition; dmd.aspetjournals.org paritaprevir/ritonavir plus dasabuvir with RPV is not recommended as such, coadministration with ATV/r is not recommended. (Viekira Pak, 2017). A reduced dose of daclatasvir (20 mg) was used to study the A higher RPV AUC (84%) was observed after administration with interaction between daclatasvir and ATV/r, which resulted in lower glecaprevir/pibrentasvir, although it was not considered clinically daclatasvir AUC (30%) and Cmax (55%) with ATV/r relative to the relevant and supports coadministration with RPV-containing regimens standard daclatasvir dose (60 mg) alone; there was no change in ATV/r (Mavyret, 2017). pharmacokinetics. Based on these data, 30 mg daclatasvir is recom-

mended when used with ATV/r (strong CYP3A inhibitors); coadmin- at ASPET Journals on September 28, 2021 Protease Inhibitors istration of 60 mg daclatasvir with DRV/r or unboosted ATV (moderate Protease inhibitor–based regimens for HIV containing ATV, DRV, or CYP3A inhibitors) warrants monitoring for daclatasvir adverse events lopinavir (LPV) have demonstrated virologic potency and a high genetic (Bifano et al., 2012; Daklinza, 2017). barrier to resistance (https://aidsinfo.nih.gov/guidelines/html/1/adult- When ombitasvir/paritaprevir/ritonavir plus dasabuvir was adminis- and-adolescent-arv/11/what-to-start). These protease inhibitors are tered simultaneously with ATV, paritaprevir AUC was 94% higher, CYP3A substrates and are administered with a pharmacokinetic booster whereas ombitasvir and dasabuvir pharmacokinetics were unchanged. (ritonavir [/r] or COBI [/c]) to increase systemic exposure (i.e., ATV/r or Paritaprevir is administered with ritonavir to boost its exposure; but as ATV/c, DRV/r or DRV/c, LPV/r). ATV/r inhibits CYP3A, UGT1A1, demonstrated in this DDI, paritaprevir is susceptible to further increase P-gp/BCRP, and OATP1B1/1B3 (Reyataz, 2017). DRV/r inhibits in the presence of a second CYP3A and/or OATP inhibitor like ATV. CYP3A, CYP2D6, and P-gp (Olysio, 2017). LPV/r inhibits CYP3A, Per the prescribing information, coadministration of ATV with ombitasvir/ P-gp, and OATP1B1/3 (http://www.fda.gov/downloads/Drugs/ paritaprevir/ritonavir plus dasabuvir should only be given in the morning GuidanceComplianceRegulatoryInformation/Guidances/UCM292362. (USPI; Viekira Pak, 2017) or if administered at the same time (SmPC; pdf). Since protease inhibitor–based regimens are administered to Viekirax, 2018). Exposures of all DAAs were lower after administration of HCV/HIV coinfected patients and have a higher potential for ombitasvir/paritaprevir/ritonavir plus dasabuvir with DRV/r twice daily, and interactions than other ARV classes, assessment of DDIs is needed DRV Ct was also 43% to 46% lower. Coadministration of DRV/r with to inform dosing recommendations. ombitasvir/paritaprevir/ritonavir plus dasabuvir is not recommended per After administration of DRV/r with simeprevir, a higher DRV Cmin the USPI; in the European Union, DRV may be administered at the same (31%) and ritonavir AUC (32%) and Cmax (23%) were observed time as ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekirax, 2018). compared with DRV/r alone (Ouwerkerk-Mahadevan et al., 2012b). Administration of LPV/r either together with, or staggered 12 hours from, Simeprevir exposure was significantly higher (AUC 159%) after the morning dose of ombitasvir/paritaprevir/ritonavir plus dasabuvir resulted coadministration with DRV/r compared with 150 mg simeprevir alone. in higher paritaprevir AUC (87%–117%) and is not recommended Use of simeprevir with any HIV protease inhibitor is not recommended (Viekira Pak, 2017). (Olysio, 2017). Elbasvir and grazoprevir were evaluated for interactions with ATV/r, Administration of sofosbuvir with DRV/r resulted in higher sofosbu- DRV/r, and LPV/r. Due to a significantly higher observed grazoprevir vir AUC (34%) and Cmax (45%), with no change in DRV, ritonavir, or AUC (650%–1186%) that may increase the risk of ALT elevations, use GS-331007 exposure. The higher sofosbuvir exposure was likely of these boosted protease inhibitors is contraindicated (Zepatier, 2018). mediated by ritonavir-mediated P-gp/BCRP inhibition (Kirby et al., The impact of several boosted protease inhibitors on glecaprevir/ 2012). DDI assessment with ledipasvir/sofosbuvir and boosted protease pibrentasvir pharmacokinetics was evaluated. Coadministration of inhibitors was conducted using complete HIV regimens of ATV/r or glecaprevir/pibrentasvir with ATV plus ritonavir resulted in higher DRV/r plus FTC/TDF (German et al., 2015). The ledipasvir AUC was glecaprevir AUC ($553%) and Cmax ($306%) and higher pibrentasvir higher (96%) when coadministered with ATV/r plus FTC/TDF, likely AUC ($64%) and Cmax ($29%); the coadministration of glecaprevir/ The DDI Potential of HCV DAAs 1223 pibrentasvir with ATV plus ritonavir is contraindicated. Coadministra- pibrentasvir, or sofosbuvir with daclatasvir, simeprevir, ledipasvir, or tion with DRV plus ritonavir resulted in higher glecaprevir AUC (397%) velpatasvir;) and up to five drugs (e.g., ombitasvir/paritaprevir/ritonavir and Cmax (209%) with no change in pibrentasvir, whereas coadminis- plus dasabuvir with or without ribavirin). Because HCV-infected tration with LPV plus ritonavir resulted in higher glecaprevir AUC individuals may use multiple medications for various ailments, the (338%) and Cmax (155%) and higher pibrentasavir AUC (146%) and consideration of DDIs is critical for selection of a safe and effective Cmax (40%). Coadministration of glecaprevir/pibrentasvir with either regimen to treat HCV. DRV plus ritonavir or LPV plus ritonavir is not recommended. The complexity of DDIs with DAA regimens varies significantly but can be clinically managed with knowledge. Sofosbuvir is a substrate for Integrase Inhibitors efflux transporters but is not a perpetrator of transport- or metabolizing – Integrase inhibitor–based regimens containing dolutegravir (DTG), enzyme (e.g., P450, UGT) mediated interactions. Generally, NS5A EVG, or raltegravir (RAL) are potent third agents in HIV regimens, are inhibitors perpetrate transport-mediated but not enzymatic interactions well tolerated, and have low DDI potential (https://aidsinfo.nih.gov/ and are not subject to many interactions requiring dose adjustment or guidelines/html/1/adult-and-adolescent-arv/11/what-to-start). In vitro, restricted use except for inducers of P450s or efflux transporters. DTG inhibits organic cation transporter OCT2, multidrug and toxin Interactions with HCV protease inhibitors can be complex, because they extrusion protein MATE1, and organic anion transporters OAT1 and are generally sensitive to OATP and/or CYP3A inhibition and can OAT3 and is a UGT1A1 and CYP3A substrate (Tivicay, 2017). In vitro, perpetrate both transport- and enzyme-mediated (e.g., CYP, UGT) interactions and can be amplified if ritonavir is used to support the DAA

EVG is a modest CYP2C9 inducer and a CYP3A substrate (Stribild, Downloaded from 2017). RAL is a UGT1A1 substrate with low propensity to affect other regimen. compounds (Isentress, 2015). Bictegravir inhibits OCT2 and MATE1 In summary, the availability of multiple highly effective DAA and is a substrate of UGT1A1 and CYP3A (Biktarvy, 2018). regimens has resulted in significant progress in curing large numbers Administration of simeprevir with RAL resulted in no interactions of patients living with chronic HCV infection. The potential for DDIs (Ouwerkerk-Mahadevan et al., 2012a). Administration of ledipasvir/ is an important consideration when identifying an optimal treatment sofosbuvir with EVG (as EVG/COBI/FTC/TDF) resulted in no interac- regimen for individual patients. dmd.aspetjournals.org tion with EVG; although higher ledipasvir (78%), sofosbuvir (36%), and GS-331007 (44%) exposures were observed, all were attributable to Acknowledgments COBI and none warranted dose adjustment (Garrison et al., 2015). We gratefully acknowledge Svetlana Markova for editorial contributions to Administration of ledipasvir/sofosbuvir with RAL or DTG resulted in no this manuscript. interactions (Kirby et al., 2012; German et al., 2014c; Garrison et al., 2015). No clinically significant interactions were observed between Authorship Contributions sofosbuvir/velpatasvir and RAL, DTG, or EVG from EVG/COBI/FTC/ Wrote or contributed to the writing of the manuscript: Garrison, German, TAF or EVG/COBI/FTC/TDF (Mogalian et al., 2016c, 2018). Similarly, Mogalian, Mathias. at ASPET Journals on September 28, 2021 no clinically significant interactions were observed between sofosbuvir/ velpatasvir/voxilaprevir and bictegravir/FTC/TAF or EVG/COBI/FTC/ References TAF, supporting coadministration (Vosevi, 2017a; Biktarvy, 2018). Badri P, Dutta S, Coakley E, Cohen D, Ding B, Podsadecki T, Bernstein B, Awni W, and Menon R Administration of daclatasvir with DTG resulted in 33% higher DTG (2015) Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when exposure, with no change in daclatasvir exposure (Song et al., 2015). coadministered with ABT-450, ombitasvir, and dasabuvir. Am J Transplant 15:1313–1322. Bifano M, Adamczyk R, Hwang C, Kandoussi H, Marion A, and Bertz RJ (2013) Daclatasvir Administration of ombitasvir/paritaprevir/ritonavir plus dasabuvir pharmacokinetics in healthy subjects: no clinically relevant drug-drug interaction with either with RAL or DTG resulted in a higher RAL (134%) or DTG (38%) cyclosporine or tacrolimus [Poster]. 64th Annual Meeting of the American Association for the Study of Liver Diseases;2013Nov1–2; Washington, DC. AUC due to UGT1A1 inhibition by ombitasvir, paritaprevir, and Bifano M, Hwang C, Oosterhuis B, Hartstra J, Tiessen RG, Velinova-Donga M, Kandoussi H, dasabuvir and/or CYP3A inhibition by ritonavir (Khatri et al., 2014b, Sevinsky H, and Bertz R (2012) Assessment of HIV antiretroviral drug interactions with the HCV NS5A replication complex inhibitor daclatasvir demonstrates a PK profile which supports 2016). No RAL or DTG dose adjustment is required (Viekira Pak, coadministration with tenofovir, efavirenz and atazanavir/r [Poster]. 19th Conference on Ret- 2017). roviruses and Opportunistic ;2012Mar5–8; Seattle, WA. Bifano M, Sevinsky H, Hwang C, Kandoussi H, Jiang H, Grasela D, and Bertz R (2014) Effect of No clinically significant interactions were observed with elbasvir and the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive grazoprevir administered with DTG or RAL. Use of EVG/COBI/FTC/ containing ethinyl estradiol and norgestimate. Antivir Ther 19:511–519. TDF is not recommended with elbasvir/grazoprevir due to the presence Biktarvy. (2018) Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use (USPI). Gilead Sciences Inc., Foster City, CA. of COBI within the regimen. Daklinza. (2014) Daklinza (daclatasvir) tablets 60 mg (Japan Prescribing Information). Bristol- Higher glecaprevir AUC (205%) and C (150%) and higher Myers Squibb K.K., Tokyo. max Daklinza. (2017) Daklinza (daclatasvir) tablets, for oral use (USPI). Bristol-Myers Squibb Co., pibrentasvir AUC (57%) were observed after coadministration of Princeton, NJ. glecaprevir/pibrentasvir with EVG/COBI/FTC/TAF; no dose adjust- Daklinza. (2018) Daklinza 30 mg film-coated tablets, daklinza 60 mg film-coated tablets (SmPC). Bristol-Myers Squibb Pharmaceutical Ltd., Middlesex, UK. ment is required for their coadministration. RAL AUC and Cmax values Eley T, Gardiner DF, Persson A, He B, You X, Shah V, Sherman D, Kandoussi H, Sims KD, were 47% and 34% higher, respectively, after coadministration with Pasquinelli C, et al. 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Gilead Sciences significant cause of premature death via liver cirrhosis, functional Inc., Foster City, CA. Epivir. (2013) Epivir (lamivudine) tablets and oral solution (USPI). GlaxoSmithKline, Research failure, or hepatocellular carcinoma. Historical HCV treatments were Triangle Park, NC. poorly tolerated and insufficiently efficacious. Recently developed anti- Garimella T, You X, Wang R, Huang SP, Kandoussi H, Bifano M, Bertz R, and Eley T (2016) A review of daclatasvir drug-drug interactions. Adv Ther 33:1867–1884. HCV therapies have consisted of combinations of all-oral regimens that Garrison KL, Custodio JM, Pang PS, Das M, Cheng F, Ma GJ, and Mathias A (2015) Drug include at least two (e.g., elbasvir and grazoprevir, glecaprevir and interactions between anti-HCV antivirals ledipasvir/sofosbuvir and integrase strand transfer 1224 Garrison et al.

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Mogalian E, Brainard D, McNally J, Shen G, Cuvin J, and Mathias A (2014) Lack of clinically German P, Moorehead L, Pang P, Vimal M, and Mathias A (2014a) Lack of a clinically important relevant pharmacokinetic drug-drug interaction between norgestimate/ethinyl estradiol and pharmacokinetic interaction between sofosbuvir or ledipasvir and hormonal oral contraceptives pangenotypic HCV NS5A inhibitor GS-5816 in HCV-uninfected female subjects [Poster 1998]. norgestimate/ethinyl estradiol in HCV-uninfected female subjects. JClinPharmacol54: 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver 1290–1298. Meeting;2014Nov7–11; Boston. 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Khatri A, Wang T, Wang H, Podsadecki T, Trinh R, Awni W, Dutta S, and Menon R (2014b) Ouwerkerk-Mahadevan S, Sekar V, Peeters M, and Beumont-Mauviel M (2012a) The pharma- Drug-drug interactions of the direct acting antiviral regimen of ABT-450/r, ombitasvir and cokinetic interactions of HCV protease inhibitor TMC435 with rilpivirine, tenofovir, efavirenz or dasabuvir with HIV protease inhibitors [Poster]. 54th Interscience Conference on Antimicrobial raltegravir in healthy volunteers [Presentation]. 19th Conference on Retroviruses and Oppor- Agents and Chemotherapy; 2015 Sep 5–9; Washington, DC. tunistic Infections;2012Mar5–8; Seattle, WA. Kim WR, Lake JR, Smith JM, Skeans MA, Schladt DP, Edwards EB, Harper AM, Wainright JL, Ouwerkerk-Mahadevan S, Sekar V, Simion A, Peeters M, and Beumont-Mauviel M (2012b) The Snyder JJ, Israni AK, et al. (2017) OPTN/SRTR 2015 annual data report: liver. 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